Gulf War Veterans' illness (GWVI) continues to cause suffering and disability for many Veterans decades after returning from their deployment. Although the major GWVI symptoms clearly point to persistent biologic nervous system abnormalities, the limited neurobiological studies to date of nervous system function and structure in GWVI have not yet clearly demonstrated pathobiologies that can guide treatment development. This application incorporates neuroscientific advances in neuroimaging, genetics, pain and sleep physiology, neuroendocrinology and neurodegeneration biomarker development in a multidisciplinary approach to defining neurobiologic abnormalities underlying GWVI symptomatology. Rationale for this effort is strengthened by our neuroimaging evidence of reduced brain metabolism and cerebrospinal fluid (CSF) biomarker evidence of neuronal damage in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND)-deployed Veterans who had no lifetime history of traumatic brain injury or posttraumatic stress disorder. A multidisciplinary group of neuroscientists will address the following Specific Aims: Specific Aim 1. To identify in GWVI abnormalities in brain structural and functional integrity. Hypothesis 1a - GWVI is characterized by decreased cerebral glucose metabolism in brain regions relevant to cognition (e.g., medial temporal lobes) using fluorodeoxyglucose-positron emission tomography; decreased structural and compositional structural integrity using magnetic resonance imaging diffusion tensor imaging and macromolecular proton fraction mapping; and decreased brain regional connectivity among nodes of the ventral and dorsal attention networks on blood oxygen level dependent functional connectivity MRI. Hypothesis Ib - GWVI is characterized by changes in CSF biomarkers associated with neurodegeneration (decreased Ab42, increased CSF total tau and phosphorylated tau (ptau181) and oxidative damage (increased F2-isoprostanes), and decreases in the neurotrophin, brain derived neurotrophic factor, Hypothesis Ic - GWVI is characterized by deficits on challenging neurocognitive tasks that assess prospective memory, cognitive processing speed, and multitasking. Specific Aim 2. To identify in GWVI abnormalities in central and peripheral systems regulating pain perception, fatigue, and sleep. Hypothesis 2a: GWVI is characterized by increased pain sensitivity by Quantitative Sensitivity Testing and impaired activation of endogenous opioids in response to Conditioned Pain Modulation. Hypothesis 2b: GWVI is characterized by abnormalities in neuropeptides, neurotransmitters, hormones, and immune factors associated with pain and fatigue perception and sleep. Hypothesis 2c: GWVI is characterized by decreased cerebral glucose metabolism in brain regions modulating sensory pain (e.g., thalamus). Specific Aim 3. To identify in GWVI genetic variants and/or epigenetic alterations associated with neurodegeneration, impaired pain processing, and metabolism of organophosphates. Hypothesis 3a: GWVI is characterized by increased frequency of the apolipoprotein E (APOE)-e4 - allele, the microtubule associated protein tau (MAPT) H1 haplotype, the Met allele of the brain derived neurotrophic factor Val66Met variant, the Val allele of the catechol-O-methyl transferase Val158Met variant, the G allele of the mu opioid receptor 1 A118G single nucleotide polymorphism (i.e., rs1799971), the Arg allele of the paraoxonase 1 (PON1) Gln192Arg variant, and decreased functional activity of PON1. Hypothesis 3b: GWVI is characterized by altered DNA methylation levels in CpG Islands in the PON1, APOE, MAPT, and BDNF genes.